Pain prevalence rates in cancer patients are high . Many will require opioids for their pain during their treatment pathway and opioids remain the most effective form of pain relief. However, the effect of opioids on cancer progression, metastases, and recurrence is increasingly being questioned. Opioid receptors are expressed on cells out with the nervous system, and they are present on cancer cells. In animal models, stimulation of these receptors can result in cancer cell stimulation. However, the story is complex. Opioid receptors are present on many cells that make up the milieu in which cancer cells exist in vivo. Opioid-induced immunomodulation can reduce CD8+ and natural killer (NK) cells facilitating tumour immunoevasion, cause changes in proinflammatory cytokines, and promote angiogenesis. However, some actions on the immune system may not promote tumour development, and are effectively anticancer and equally may not actually be opioid receptor-mediated. Furthermore, the ability of opioids to negate or minimise the highly deleterious effect of pain and stress on cancer progression needs to be borne in mind.
Opioids and the immune system
Morphine and other opioids have been shown to have a variety of effects on the immune system and to understand their impact on cancer, we must understand normal interactions between immune and tumour cells (Fig. 1).
From Paul Erlich's ‘magic bullets’ to the immunosurveillance theories of Burnet and Thomas, the immune system plays a pivotal role in cancer control. More recent iterations have incorporated the role of the adaptive and innate immunities in policing cancer. There is a balance of mechanisms that are both tumour suppressive and promoting which has being coined ‘cancer immunoediting’ .
Cancer cells have undergone genetic changes that release them from normal apoptotic control. These differences are potentially identifiable as nonself by the immune system. However, not all cancer cells express these immunogenic nonself ‘transplantation rejection antigens’ and several distinct mechanisms contribute to the failure of immune-mediated cancer suppression.
- Vascular endothelial cells within tumours may not express the requisite adhesion molecules for cytotoxic lymphocytes (CTLs) and similar cell function .
- Other immune regulatory systems designed to temper overzealous auto-immune activity (e.g. regulatory T cells, Tregs) are often increased in cancer, can interfere with anticancer immune processes (e.g. T-cell immunity) and may be associated with a poorer prognosis . The biology of Tregs exhibits dichotomy since they promote tumour growth by suppression of antitumour immunity yet by reducing procancer inflammatory stress may hinder tumourgenesis .
- Tumour cells can be immunosuppressive through release of soluble factors and by expression of moieties on cell surfaces such as transforming growth factor-β (TGF-β)  which may contribute to poor outcomes .
- Activation of proinflammatory immune systems can be involved in oncogenesis , and chronic inflammation (e.g. from tobacco smoke) is associated with 20% of all cancers. Chronic inflammation promotes oncogenic mutations, increases cellular growth, and stimulates angiogenesis . In contrast to the cytolytic anticancer actions of CD8+ cells, a subpopulation of CD8+ cells promotes tumourgenesis, and is implicated in chronic inflammation-induced cancers . Acute inflammation may in itself be actively anticancer and forms the basis of some therapies.
- Immunoediting: Removal by the immune system of the most immunogenic tumour cells leaves (less immunogenic) ‘edited’ cells. These are less likely to be detected and removed by subsequent immunosurveillance . ‘Edited’ cells subsequently implanted into immunocompetent mice have been shown to be more likely to result in tumour growth than the ‘unedited’ cells that were still immunogenically ‘visible’ to tumour surveillance systems .
Three phases of immunoediting have been described .
Innate immunity can be activated by early tumour cell ligand expression, which activates a tumour-targeting adaptive immune response. Although innate systems can remove certain early tumour cells, typically both innate and adaptive (including the propagation and expansion of CD4+ and CD8+ T cells) are required. NK cells are an integral part of the tumour ligand-activated innate response.
Tumour cells that escape elimination are ‘kept in check’ by the adaptive immune system but retain the potential to develop into tumours if the equilibrium is unbalanced. The pivotal role of the adaptive system is highlighted by the development of latent tumours after immune system compromise (e.g. reduction of CD4+ and CD8+ cells) [13,14].
Escape from equilibrium is likely to be achieved by immunoevasive cells. Cancer immunosuppression may be mediated by diminution of antigen expression/processing and abetted by the editing-driven selection of immunologically ‘invisible’ cells. Local microenvironment changes by suppressive cytokines [e.g. vascular endothelial growth factor (VEGF) and TGF-β] and recruitment of inhibitory cell systems (Tregs) are also implicated . However, it is not simply the presence or absence of CTLs but a complex interplay of infiltrating CD8+, NK cells and tumour-associated macrophages that determines whether escape is likely .
There are three distinct classical opioid receptors: mu opioid receptor (MOR) (μ), kappa opioid receptor (KOR) (κ), and delta opioid receptor (DOR) (δ). These G protein coupled receptors are expressed widely in the central nervous system (CNS), especially in areas germane to pain . However, there may also be expression on many elements of the immune system , (although this concept has been questioned) [18▪▪]. A fourth receptor, the opioid receptor-like (ORL-1 or nociceptin opioid receptor) receptor has been identified . Nociceptin (or orphanin FQ) is the endogenous ligand and opioid receptor-like-1 may be preferentially expressed on immune cells .
There is evidence for opioid receptor involvement in cancer progression and outcome. MOR over expression is observed in certain cancer cell lines and polymorphism of the MOR (A118G exhibits reduced receptor response to opioid binding) is associated with decreased breast cancer mortality [21▪▪].
Many actions of opioids are mediated through nonclassical receptors (demonstrated by lack of reversal by classical opioid receptor antagonists) and may contribute to opioid actions.
EFFECTS OF OPIOIDS ON KEY IMMUNE CELLS INVOLVED IN ANTITUMOUR IMMUNE EFFECTS
Although there are exceptions, organized CTLs play a major role in tumour control . Morphine inhibits activation of CTLs, especially CD4+CD8+ cells . Both immature and mature/differentiated T cells are reduced significantly by morphine treatment (including cytotoxic CD8+ cells) in part mediated by a morphine-induced increase in corticosteroids . Poorly controlled pain and other stressors contributing to rises in endogenous corticosteroids makes the opioid effect difficult to separate out.
Further evidence for opioid-mediated, cancer promoting actions on CTLs is supported by antagonism of MOR and DOR decreasing mammary cancer progression and increasing NK cell activation . However, in-vitro morphine can increase CTL function, especially CD8+ cells, and modulate a potential anticancer effect .
Human data are similarly conflicted. Low-dose intrathecal morphine can inhibit NK cell activity . However, blood from chronic morphine users showed no difference in NK cytolytic activity compared with opioid-naïve controls [28▪] and in some models morphine can ‘increase’ cytolytic activity in NK cells .
The mast cell is the conductor of the immunosurveillance microenvironment, causing context dependent pro and anticancer actions . Morphine is suppressive of mast cells and reduces function in some models of inflammation . However, morphine can activate mast cells [32▪] and raise histamine by a non-MOR-mediated action .
OPIOID MODULATION OF CYTOKINES AND CHEMOKINES
Chronic morphine increases TGFβ resulting in a reduction of IL-2 and IFNγ mediated by MOR . IL-2 is especially important in the maturation and differentiation of CD4+CD8+ cells and NK cell activity, and therefore this anti-inflammatory action could result in cancer promotion. However, TGFβ can be proinflammatory . Morphine can also stimulate proinflammatory cytokines, while reducing anti-inflammatory ones (IL-10) . MOR activation increases some chemokines [chemokine ligand receptor 5 (CCL5) and chemokine (C-X-C motif) receptor 4] via increased TGFβ synthesis . CCL5 is proinflammatory, promoting T-cell chemotaxis and stimulating NK cell cytotoxicity .
Other opioid-mediated actions, such as ‘reduction’ of the proinflammatory IL-1, IL-6, and TNFα, are influenced by different opioid receptor types. This anti-inflammatory action is KOR mediated .
Microglia are part of the immune system of the CNS and morphine activates microglia via the Toll-like receptor 4 (‘the endogenous danger signal’ receptor), which results in release of proinflammatory cytokines .
Anti-inflammatory actions can promote cancer by reducing immunosurveillance but inflammatory changes may be necessary steps in cancer development. Both pro and anti-inflammation morphine actions can potentially have inhibitory and stimulatory effects on cancer progression.
EFFECTS OF OPIOIDS ON ANGIOGENESIS, MIGRATION/INVASION, METASTASIS, AND APOPTOSIS
Evidence of opioid effects on tumour growth, angiogenesis, migration, and metastasis is inconsistent and contradictory. Interpretation of the studies is influenced by timing and dosage. Angiogenesis is only a prerequisite for continued growth when the tumour mass reaches approximately 1 × 106 cells . Conclusions drawn from studies where early growth differences were observed should be interpreted with caution.
Differences in morphine dosage also have a significant impact. Very high doses of morphine are cytotoxic  and the clinical relevance of those utilized in studies needs to be assured.
Tumour-induced proliferation of endothelial cells is mediated by upregulation of angiogenic growth factors (VEGF). This upregulation occurs as a result of localized hypoxia in the tumour microenvironment [via Hypoxia Inducible Factor 1α (HIF1α)], but also directly by proto-oncogenes (e.g. the ras family).
Opioids can enhance tumour-induced angiogenesis. Morphine stimulates the VEGF receptor through MOR. Singleton found that morphine, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (MOR agonist) and VEGF all stimulated proliferation and migration of human microvascular cells. The MOR receptor antagonism prevented this effect as did VEGF tyrosine kinase inhibition . Gupta showed in human endothelial cells, morphine activates mitogen-activated protein kinase/extracellular signal regulated kinase phosphorylation to produce cell proliferation via a nitric oxide-dependent pathway, analogous to that activated by VEGF . This is opioid receptor-mediated, but was also observed with DOR and KOR agonists. Morphine-treated mice also showed accelerated breast tumour growth associated with increased vascularization . Coadministration of naloxone with morphine-inhibited tumour growth but did not inhibit the angiogenic effect, suggesting a possible separate naloxone-specific antitumour effect. As above, Gupta's group also found that concentrations (much higher than clinical) were cytotoxic to endothelial cells  (Fig. 2).
More recently, mice with invasive breast carcinoma receiving morphine over 7 weeks showed a marked increase in angiogenesis. This study demonstrated an increase in cytokine release, substance P and mast-cell activation, which may have increased growth and angiogenesis [32▪].
Although this evidence supports the concept of morphine-induced angiogenesis, the literature is not consistent. Koodie found that morphine administered in clinically relevant plasma concentrations to the Lewis Lung carcinoma model, resulted in an inhibition of angiogenesis by reduction of HIF1α. This effect was opioid receptor dependent .
Moreover, data also suggest different opioid receptor effects. KOR agonists inhibit angiogenesis by suppressing VEGF expression in human endothelial cells. Furthermore, KOR knockout mice with melanoma or lung cancer showed enhanced angiogenesis relative to wild-type mice, whereas the wild-type showed enhanced KOR expression (but nor MOR or DOR), suggesting that KOR could play a role as an antiangiogenic mediator in tumours [45▪].
MIGRATION/INVASION AND METASTASIS
Data concerning the effect of opioids on tumour cell migration and proliferation are also conflicting. Although Harimaya  found that morphine decreased metastasis of colon cancer cells by decreasing migration and adhesion, a study involving three cancer cell types (including colonic) found no opioid effect . By contrast, in a further study, morphine promoted cell migration and proliferation of breast adenocarcinoma cells via a nonopioid receptor dependent action . Additionally, antagonism at peripheral MOR resulted in cancer cell inhibition in human nonsmall-cell lung cancer (NSCLC) lines .
A crucial step in the migration of cancer cells is degradation of the extracellular matrix by urokinases and matrix metalloproteinases (MMPs) which facilitate passage through the basement membrane, a sine qua non of metastasis. Urokinase plasminogen activator and its receptor are raised in many cancers [50–52] and morphine augments its secretion [53–55]. Raised MMP levels are associated with advanced tumour stage and presence of metastasis . Interestingly, morphine has been found to decrease MMP2 and MMP9 levels in breast cancer cells via a nonopioid receptor pathway and in another study decreased MMP9 and increased the endogenous MMP inhibitor tissue inhibitor of metalloproteinase 1 (TIMP-1) [57▪]. This raises the possibility that morphine can be antimetastatic through a nonopioid receptor-mediated inhibition of extracellular matrix degradation.
Cancer-mediated inhibition of apoptosis (programmed cell death) is key to tumour survival. Evidence suggests that opioids enhance apoptosis implying a possible additional antitumour action to that suggested above. Opioid receptor-mediated apoptosis has been demonstrated in breast cancer cells  and in small cell lung cancer cells via DOR and KOR . Morphine (via MORs)-induced expression of Fas (a transmembrane receptor of the tumour necrosis factor family) in immune cells priming them for Fas ligand-mediated apoptosis . Furthermore, proliferation of prostate cancer cells was inhibited in a dose-dependent manner by etorphine (a nonselective opioid agonist) and morphine and antagonized in some cases by a nonselective opioid antagonist, indicating both opioid receptor and nonopioid receptor dependent pathways on apoptosis promotion .
However, different opioid concentrations induce differential actions in apoptosis. Hayashi's group observed a DOR-mediated protection of phaeochromocytoma cells against cell death in femtomolar to picomolar concentrations but was cytotoxic via MOR-induced Fas-ligand activation at higher concentrations . In another study, use of clinically relevant concentrations of morphine-induced apoptosis in different cancer cells . Supratherapeutic doses were cytotoxic. Similarly, Tegeder  reported therapeutic concentrations of morphine inhibited breast cancer cell progression but higher doses were cytotoxic via an opioid receptor-independent pathway. In some models, morphine may actually promote cell proliferation or have a much reduced proapoptotic effect (including reducing the effects of coadministered proapoptotic chemotherapeutic agents) [65,66].
STRESS AND CANCER PROGRESSION
Surgical stress has a profound influence on the immune system increasing potential for metastasis  and cancer progression . Indeed stress of multiple causes has been shown to do the same, putatively mediated by immunological inhibition . Increases in stress hormones with consequent stimulation of many procancer mediators (including VEGF) are in part responsible for these observations . In addition, glucocorticoids are profoundly immunosuppressive to both the innate and adaptive systems. However, effects on the hypothalamic–pituitary–adrenal (HPA) axis are notoriously difficult to study because of numerous potential modulators of glucocorticoid production .
The indirect action of opioids on the immune system via the HPA axis is also dogged with conflicting evidence and sensitivity to differences in opioid dose and chronicity . Acute exposure to high-dose opioid (morphine 2 mg/kg) in rats was shown to increase adenocorticotrophic hormone (ACTH) yet 0.5 mg/kg had no effect .
In contrast, in humans a single dose of oral morphine decreased ACTH and cortisol . Longer term administration of a wide range of morphine doses (30–240 mg for 1–12 weeks) reduced the elevated ACTH and cortisol levels in pain patients . Here, opioids are protective against the glucocorticoid-mediated immunosuppressive effect. However, complexities of HPA axis function, such as diurnal variation, makes these observations difficult to assess.
COMPARISON WITH NONMORPHINE OPIOIDS
Most research into immunological action of opioids has focused on morphine. However, comparative studies have suggested that certain opioids may be less immunoactive with less potential adverse affects on cancer immunosurveillance. Sacerdote looked at the action of several opioids on NK cell activity and IL-2 production and found morphine but not oxycodone had a powerful immunosuppressive effect. The MOR and KOR agonist nalorphine was strongly immunosuppressive but only mildly antinociceptive . The antinociceptive effect was reduced by a KOR antagonist independently of the immunosuppressive action .
Tramadol significantly reduced lung metastasis in a rat model by reversing surgery-induced NK cell inhibition as well as stimulating NK cell activity in nonoperated animals . Morphine and fentanyl stimulated the HPA axis, reduced NK cell activity and enhanced metastasis in unoperated rats, yet buprenorphine did not. Buprenorphine also reduced the surgical stress-induced suppression of NK cell activity and ameliorated the resulting increase in lung metastasis of an NK cell-sensitive tumour . Unlike fentanyl, buprenorphine had no effect after acute administration on several splenic cellular immune processes, including NK cell activity and IL-2 production . In the same study, administration of fentanyl or buprenorphine chronically (7 days) was not associated with immunosuppression. Such tolerance suggests that the immunomodulation of perioperative ‘acute’ opioid administration may be fundamentally different to chronic opioids. However, a buprenorphine-MOR-mediated and dose-dependent immunosuppression (including reduced NK cell activity) has been reported .
Notably, remifentanil, a rapid onset/offset opioid used in the intraoperative setting, seems also to have little effect on immune function .
Despite the wealth of, albeit conflicting, data in preclinical models, there are relatively few clinical studies on the effect of opioids on cancer growth, recurrence or survival. A multitude of contributory factors, especially pain per se, makes elucidation of the specific action of opioids difficult.
Reduction of total opioid use associated with intrathecal morphine was compared with comprehensive medical management in patients with refractory cancer pain [82▪▪]. The reduction in total opioid dose appeared to correlate with an increased cancer survival. After breast cancer surgery, paravertebral rather than morphine analgesia, was associated with significantly reduced cancer recurrence .
Also looking at the effect of chronic opioids, 113 nonsurgical, advanced prostate cancer patients demonstrated increased opioid requirements that were associated with worse progression-free survival and worse overall survival  although more aggressive disease could have resulted in greater pain and increased opioid needs.
Although increased VEGF is implicated in morphine procancer action, reduction of morphine use through the use of a paravertebral block had no effect on VEGF . Patients who had a local anaesthetic epidural infusion for prostate cancer surgery experienced a 57% reduction in biochemical cancer recurrence compared with an opioid-using group  yet in a methodologically similar retrospective analysis after the same surgical intervention, no difference was found . Hiller and colleagues  found that ‘effective’ epidural analgesia in patients undergoing oesphago-gastrectomy also had a survival benefit and decreased time to recurrence of gastro-oesophageal cancer. Another retrospective analysis in 1642 patients having radical prostatectomy detected increased cancer progression and decreased survival associated with not having neuraxial blockade [89▪]. It is difficult to conclude that this effect was related to a reduction in opioid consumption as the patient in the epidural group still received significant doses of intravenous morphine (mean 20 mg compared with 40 mg in the patients without epidural).
A meta-analysis of colorectal cancer patients comparing epidural to a general anaesthetic alone for perioperative pain management showed a significant improvement in overall survival associated with an epidural but no effect on recurrence-free survival . The authors could not conclude that the epidural influenced the control of cancer. Similarly, a retrospective analysis of over 42 000 patients having surgery for nonmetastatic colorectal cancer identified a link between epidural and improved survival but no effect on recurrence .
Several other retrospective perioperative studies failed to show a survival benefit using opioid sparing, neuraxial/regional techniques after lung cancer surgery  surgery for colorectal cancer  or ovarian cancer  or brachytherapy treatment .
Similarly, there was no protective effect of reduction of morphine from regional blockade after radial open prostatectomy . One ‘prospective’ study examined 503 patients who had major abdominal surgery for cancer (MASTER trial) and failed to show any influence of epidural on survival even though the epidural group received a median of 0 mg morphine compared with 107 mg in the controls [97▪].
Recently two meta-analyses have been published reviewing most (but not all) of the literature for the effect of neuraxial blockade on mixed cancer surgery and specifically surgery for colonic carcinoma [98▪▪,99▪]. Pei [98▪▪] suggested that there may be a benefit for neuraxial blockade for surgery for prostate cancer but there was no evidence for such a link with colonic cancer. Only two of the total of 10 studies included were prospective [98▪▪]. Vogelaar [99▪] concluded from analysis of only colonic cancer surgery that overall survival was improved by having an epidural. However, results were mixed and there was no effect on disease-free survival [99▪].
Clinical evidence concerning nonmorphine opioids. The action of morphine and tramadol on NK cell activity was investigated postoperatively in 30 patients with uterine cancer 2 h after a single i.m. dose of opioid . Both drugs were equipotent for analgesia, but while neither morphine nor surgery affected NK cell activity, tramadol was associated with a significant increase in NK cell activity. Of note, surgical stress profoundly reduced immunological competence. In 150 patients using different patient-controlled analgesia opioids, morphine, and fentanyl reduced surgery-induced nuclear factor kappa B (NF-κB) activation but tramadol did not. Morphine also reduced IL-2 yet tramadol was associated with increased IL-2 production . The opposing actions of fentanyl in vitro and in vivo and underlines the hazards of extrapolation of in-vitro results to clinical scenarios.
Multifactorial perioperative techniques to achieve optimal analgesia and resultant ‘opioid sparing’ may offer long-term benefits for cancer patients . However, most of the data is retrospective and confounded by wide variations in practice and the difficulties of providing adequate controls. It would be erroneous to extrapolate and assume similar effects for opioids chronically administered for cancer pain.
There is sufficient in vitro and animal model work to make a biologically plausible case for a detrimental effect of opioids on cancer progression. It is likely this is mediated through immunosuppression and potentiation of angiogenesis. However, there is huge variability within the evidence. Opioid dosage, chronicity of administration and the specific opioid can influence outcome, and different cancers exhibit differential responses to opioids. In-vitro studies cannot factor the effects of the complex environment that cancer cells exist, thus excluding the modulating effects of the interactions that occur in vivo. Moreover, other confounders include the inseparability of the actions of stress and morphine. Opioid receptor polymorphism may also be important in explaining differential responses in animal and humans. Alternate genotypes of the MOR may lead research into peripheral opioid receptor antagonists as a cancer treatment [21▪▪,103].
Clinical evidence is sparse but there are some retrospective data that suggest perioperative opioid sparing may lead to better long-term cancer outcomes. However, high-quality studies are needed in the perioperative environment, and in the use of opioids for chronic cancer-related pain. Research into these two areas is surely now mandatory.
High rates of pain prevalence in cancer patients and the absence of effective alternative nonopioid regimens in many cases leaves us in a conundrum. Abandoning a highly effective analgesic without a replacement is both inhumane and likely to be self defeating given the very significant adverse influence of pain and stress on cancer progression.
Financial support and sponsorship
Conflicts of interest
T.W. and P.F.S. wrote and edited the review. There was no other assistance. P.F.S. has received payment for consultancy and educational work for Pfizer, Grunenthal, and Astellas. There are no conflicts of interest.
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